Total Synthesis of the Tetrasaccharide Repeating Unit of Pseudomonas aeruginosa Serotype 4 O‐Antigen†

Comprehensive Summary Pseudomonas aeruginosa is an opportunistic pathogen responsible for cystic fibrosis, bloodstream infections and hospital‐acquired pneumonia. The O‐antigen of lipopolysaccharide on the cell surface of P. aeruginosa has been identified as a promising target for the development of carbohydrate‐based vaccines. In this study, we present the first total synthesis of the tetrasaccharide repeating unit of P. aeruginosa serotype 4 O‐antigen using a linear [((1+1)+1)+1] glycosylation strategy. All rare amino sugars were synthesized from commercially available monosaccharides. The formation of 1,2‐ cis L‐fucosamine glycosidic bonds was achieved with high efficiency and stereoselectivity by judicious choice of C3/C4‐OH protecting groups of L‐fucosamine. The N ‐phenyl trifluoroacetimidate glycosyl donors have proven to be more efficient than selenoglycoside or thioglycoside donors during glycosylation, particularly when coupling with the low‐reactivity C3‐OH group of the O4‐Bz protected L‐FucN 3 acceptor. TBSOTf has demonstrated higher efficacy as a catalyst compared to TMSOTf for promoting glycosylation with less reactive acceptors. The synthetic tetrasaccharide repeating unit of P. aeruginosa serotype 4 O‐antigen, which incorporates a pentyl amine linker at the reducing end, has been prepared for conjugation with carrier proteins or for utilization in microarray studies aimed at further immunological investigations.